Legionnaires' disease is a highly fatal pneumonia that occurs worldwide in both epidemic and endemic form. An estimated 100,000 cases occur annually in the United States. The causative bacterial agent, Legionella pneumophila, is an intracellular pathogen, and thus belongs to a group of human pathogens that are extremely important causes of morbidity and mortality worldwide. Millions of people are affected by such intracellular parasites as Mycobacterium tuberculosis, Mycobacterium leprae, Trypanosoma cruzi, Leishmania sp., Chlamydia trachomatis, and Toxoplasma gondii. Prevention and therapy for many of these diseases is unsatisfactory in part because more needs to be learned about the interaction of these pathogens with the human immune system. Legionella pneumophila infection of human mononuclear phagocytes is an excellent in vitro model for studies of intracellular parasitism, macrophage activation, and the roles of humoral and cell-mediated immunity. This proposal seeks to exploit this model to systematically explore critical aspects of the interaction between L. pneumophila and components of the human cellular and humoral immune defense system. Such studies should provide rational strategies for prevention and treatment of Legionnaires' disease and, hopefully, other diseases caused by intracellular pathogens. Specific aims are to: a) Determine the capacity of specific L. pneumophila antigens to stimulate human cell-mediated immunity; b) Determine the influence of antibody to specific L. pneumophila surface components on survival of the bacterium in human serum; c) Determine the influence of antibody to specific L. pneumophila surface antigens on the survival and multiplication of L. pneumophila in activated and nonactivated human monocytes; d) Determine the influence of antibody against specific L. pneumophila surface antigens on intracellular interactions between the L. pneumophila phagosome and cytoplasmic organelles of activated and nonactivated monocytes; e) Determine the influence of gamma interferon - activated monocytes on L. pneumophila in the presence of specific antibodies against L. pneumophial surface antigens and in the presence of antibiotics; f) Determine which of several bacterial components or products induce specific cell-mediated immunity and cutaneous delayed-type hypersensitivity in immunized guinea pigs and which induce antibody responses; g) Determine if immunization of guinea pigs with one of several L. pneumophila components or products induces protection against challenge with virulent L. pnuemophila.